Synthesis of indolylmaleimides

Abstract

The present invention provides a method for synthesizing indolylmaleimides by reacting an activated maleimide preferably with an optionally substituted organometallic-3-indole in the presence of a transition metal catalyst.

We claim: 
     
       1. A method of making an indolylmaleimide which comprises reacting an activated maleimide with an organometallic-3-indole in the presence of a palladium transition metal catalyst. 
     
     
       2. The method of claim 1 wherein said indolylmaleimide has a formula: ##STR33## wherein: R 2  is an optionally substituted indol-3-yl, R 3  is selected from hydrogen and a protecting group,   R 7  's are hydrogen or up to four optional substituents independently selected from halo, alkyl, hydroxy, alkoxy, haloalkyl, nitro, --NHCO(alkyl), and --NR 9  R 10  where R 9  and R 10  are independently hydrogen or methyl,   R 8  is hydrogen or an optional substituent selected, from an alkyl, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group; an alkylglycose residue; a group of the formulae: ##STR34## where: Het signifies a heterocyclyl group,   W signifies NH, S or a bond,   T signifies NH or S,   V signifies O, S, NH, or NCN,   A signifies alkylthio, amino, monoalkylamino or dialkylamino, and   Ar signifies aryl;   R 16  is hydrogen, alkyl, haloalkyl, acetyl, aryl, --CH(aryl) 2 , amino, monoalkylamino, dialkylamino, guanidino, --C═N(alkoxy-carbonyl))-NH-alkoxycarbonyl), amidino, hydroxy, carboxy, alkoxycarbonyl or heterocyclyl;   R 14  is hydrogen or an optionally substituted alkyl; or R 8  and R 14  are linked together through a group of the formula: ##STR35## where R 17  and R 18  are independently hydroxy, carboxy, acyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkoxycarbonyl, cyano, amidino or aminocarbonyl, and     n is 1, 2, 3, 4, 5, or 6, p and q are independently 1, 2, 3, or 4, r is 1, 2, or 3, s is 0, 1, 2, or 3, t is 1 or 2, and u is 0 or 1.   
     
     
       3. The method of claim 1 wherein said indolylmaleimide has a formula: ##STR36## wherein R 3  is selected from hydrogen and a protecting group, R 4  's and R 7  's are hydrogen or up to four optional substituents independently selected from halo, alkyl, hydroxy, alkoxy, haloalkyl, nitro, --NHCO(alkyl), and --NR 9  R 10  where R 9  and R 10  are independently hydrogen or methyl,   R 6  and R 8  are independently hydrogen or an optional substituent independently selected, from an alkyl, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group; an alkylglycose residue, a group of the formulae: ##STR37## where: Het signifies a heterocyclyl group,   W signifies NH, S or a bond,   T signifies NH or S,   V signifies O, S, NH, or NCN,   A signifies alkylthio, amino, monoalkylamino or dialkylamino, and   Ar signifies aryl;   R 16  is hydrogen, alkyl, haloalkyl, acetyl, aryl, --CH(aryl) 2 , amino, monoalkylamino, dialkylamino, guanidino, --C(═N(alkoxy-carbonyl))-NH-(alkoxycarbonyl), amidino, hydroxy, carboxy, alkoxycarbonyl or heterocyclyl;   or R 6  and R 8  are joined together via an optionally substituted alkylene moiety, optionally having an internal ether (--O--), amino (--NH--) or amide (--CONH--) linkage;   R 14  and R 15  are independently hydrogen or an optionally substituted alkyl; or R 8  and R 14  are linked together through a group of the formula: ##STR38## where R 17  and R 18  are independently hydroxy, carboxy, acyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkoxycarbonyl, cyano, amidino or aminocarbonyl, and     n is 1, 2, 3, 4, 5, or 6, p and q are independently 1, 2, 3, or 4, r is 1, 2, or 3, s is 0, 1, 2, or 3, t is 1 or 2, and u is 0 or 1.   
     
     
       4. A method of making an indolylmaleimide which comprises reacting an activated maleimide of the following formula: ##STR39## wherein R 1  is selected from a leaving group and an optionally substituted indol-3-yl, R 2  is a leaving group, and   R 3  is --H or a protecting group, with an organometallic-3-indole reagent of the following formula: ##STR40## wherein R 4  's are hydrogen or up to four optional substituents independently selected from hydrogen, halo, alkyl, hydroxy, alkoxy, haloalkyl, nitro, --NHCO(alkyl), and --NR 9  R 10  where R 9  and R 10  are independently hydrogen or methyl,     R 5  is selected from --B(OH) 2 , --ZnCl 2  and --Sn(R 13 ) 3 , wherein R 13  is selected from an alkyl and an aryl,   R 6  is hydrogen or an optional substituent selected, from an alkyl, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group; an alkylglycose residue, a group of the formulae: ##STR41## where: Het signifies a heterocyclyl group,   W signifies NH, S or a bond,   T signifies NH or S,   V signifies O, S, NH, or NCN,   A signifies alkylthio, amino, monoalkylamino or dialkylamino, and   Ar signifies aryl;   R 16  is hydrogen, alkyl, haloalkyl, acetyl, aryl, --CH(aryl) 2 , amino, monoalkylamino, dialkylamino, guanidino, --C(═N(alkoxy-carbonyl))-NH-(alkoxycarbonyl), amidino, hydroxy, carboxy, alkoxycarbonyl or heterocyclyl;   R 14  is hydrogen or an optionally substituted alkyl;   or R 6  and R 14  are linked together through a group of the formula: ##STR42## where R 17  and R 18  are independently hydroxy, carboxy, acyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkoxycarbonyl, cyano, amidino or aminocarbonyl, and   n is 1, 2, 3, 4, 5, or 6, p and q are independently 1, 2, 3, or 4, r is 1, 2, or 3, s is 0, 1, 2, or 3, t is 1 or 2, and u is 0 or 1,   in the presence of a palladium transition metal catalyst.   
     
     
       5. The method of claim 4 wherein R 2  is triflate and said reacting is conducted in the presence of a fluoride ion. 
     
     
       6. The method of claim 5 wherein R 5  is --B(OH) 2 . 
     
     
       7. A method of making an indolylmaleimide which comprises reacting an activated maleimide with an organometallic reagent in the presence of a palladium transition metal catalyst, wherein: said activated maleimide has the formula: ##STR43## wherein R 1  is selected from a leaving group and an optionally substitute indolyl,   R 2  is a leaving group, and   R 3  is --H or a protecting group, and wherein said organometallic reagent has the formula: ##STR44## wherein: R 4  's are hydrogen or up to four optional substituents independently selected from halo, alkyl, hydroxy, alkoxy, haloalkyl, nitro, --NHCO(alkyl), and --NR 9  R 10  where R 9  and R 10  are independently hydrogen or methyl,     R 5  is selected from --B(OH) 2 , --ZnCl 2  and --Sn(R 13 ) 3 , wherein R 13  is selected from an alkyl and an aryl,   R 6  is hydrogen or an optional substituent selected, from an alkyl, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group; an alkylglycose residue, a group of the formulae: ##STR45## where: Het signifies a heterocyclyl group,   W signifies NH, S or a bond,   T signifies NH or S,   V signifies O, S, NH, or NCN,   A signifies alkylthio, amino, monoalkylamino or dialkylamino, and   Ar signifies aryl;   R 16  is hydrogen, alkyl, haloalkyl, acetyl, aryl, --CH(aryl) 2 , amino, monoalkylamino, dialkylamino, guanidino, --C(═N(alkoxy-carbonyl))-NH-(alkoxycarbonyl), amidino, hydroxy, carboxy, alkoxycarbonyl or heterocyclyl;   R 14  is selected from hydrogen and an optionally substituted alkyl;   or R 6  and R 14  are linked together through a group of the formula: ##STR46## where R 17  and R 18  are independently hydroxy, carboxy, acyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkoxycarbonyl, cyano, amidino or aminocarbonyl, and   n is 1, 2, 3, 4, 5, or 6, p and q are independently 1, 2, 3, or 4, r is 1, 2, or 3, s is 0, 1, 2, or 3, t is 1 or 2, and u is 0 or 1.   
     
     
       8. The method of claim 7 wherein said indolylmaleimide has a formula: ##STR47## wherein R 3  is selected from hydrogen and a protecting group, R 4  's and R 7  's are hydrogen or up to four optional substituents independently selected from halo, alkyl, hydroxy, alkoxy, haloalkyl, nitro, --NHCO(alkyl), and --NR 9  R 10  where R 9  and R 10  are independently hydrogen or methyl;   R 6  and R 8  are independently hydrogen or an optional substituent independently selected, from an alkyl, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group; an alkylglycose residue, a group of the formulae: ##STR48## where: Het signifies a heterocyclyl group,   W signifies NH, S or a bond,   T signifies NH or S,   V signifies O, S, NH, or NCN,   A signifies alkylthio, amino, monoalkylamino or dialkylamino, and   Ar signifies aryl;   R 16  is hydrogen, alkyl, haloalkyl, acetyl, aryl, --CH(aryl) 2 , amino, monoalkylamino, dialkylamino, guanidino, --C(═N(alkoxy-carbonyl))-NH-(alkoxycarbonyl), amidino, hydroxy, carboxy, alkoxycarbonyl or heterocyclyl; or R 6  and R 8  are joined together via an optionally substituted alkylene moiety, optionally having an internal ether (--O--), amino (--NH--) or amide (--CONH--) linkage;     R 14  and R 15  are independently selected from hydrogen and an optionally substituted alkyl; or R 8  and R 14  are linked together through a group of the formula: ##STR49## where R 17  and R 18  are independently hydroxy, carboxy, acyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkoxycarbonyl, cyano, amidino or aminocarbonyl, and     n is 1, 2, 3, 4, 5, or 6, p and q are independently 1, 2, 3, or 4, r is 1, 2, or 3, s is 0, 1, 2, or 3, t is 1 or 2, and u is 0 or 1.   
     
     
       9. The method of claim 7 wherein R 2  is triflate and said reacting is conducted in the presence of a fluoride ion. 
     
     
       10. The method of claim 9 wherein R 5  is --B(OH) 2 . 
     
     
       11. The method of claim 9 wherein the fluoride ion is provided by tetrabutylammonium fluoride, potassium fluoride or cesium fluoride. 
     
     
       12. A method of making a bisindolylmaleimide of the formula: ##STR50## wherein R 3  is selected from hydrogen and a protecting group, R 4  's and R 7  's are hydrogen or up to four optional substituents independently selected from halo, alkyl, hydroxy, alkoxy, haloalkyl, nitro, --NHCO(alkyl), and --NR 9  R 10  where R 9  and R 10  are independently hydrogen or methyl;   R 6  and R 8  are independently hydrogen or an optional substituent independently selected, from an alkyl, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group; an alkylglycose residue, a group of the formulae: ##STR51## where: Het signifies a heterocyclyl group,   W signifies NH, S or a bond,   T signifies NH or S,   V signifies O, S, NH, or NCN,   A signifies alkylthio, amino, monoalkylamino or dialkylamino, and   Ar signifies aryl;   R 16  is hydrogen, alkyl, haloalkyl, acetyl, aryl, --CH(aryl) 2 , amino, monoalkylamino, dialkylamino, guanidino, --C(═N(alkoxy-carbonyl))-NH-(alkoxycarbonyl), amidino, hydroxy, carboxy, alkoxycarbonyl or heterocyclyl; or R 6  and R 8  are joined together via an optionally substituted alkylene moiety, optionally having an internal ether (--O--), amino (--NH--) or amide (--CONH--) linkage;     R 14  and R 15  are independently selected from hydrogen and an optionally substituted alkyl, or R 8  and R 14  are linked together through a group of the formula: ##STR52## where R 17  and R 18  are independently hydroxy, carboxy, acyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkoxycarbonyl, cyano, amidino or aminocarbonyl, and     n is 1, 2, 3, 4, 5, or 6, p and q are independently 1, 2, 3, or 4, r is 1, 2, or 3, s is 0, 1, 2, or 3, t is 1 or 2, and u is o or 1;   which comprises reacting an activated maleimide with an organometallic-3-indole reagent in the presence of a palladium transition metal catalyst, wherein   said activated maleimide has the formula: ##STR53## wherein R 1  is selected from an indol-3-yl group,   R 2  is a leaving group, and   R 3  is selected from hydrogen and a protecting group, and said organometallic-3-indole has the formula: ##STR54## wherein R 5  is selected from --B(OH) 2 , --ZnCl 2  and --Sn(R 13 ) 3 , wherein R 13  is selected from an alkyl and an aryl.     
     
     
       13. The method of claim 12 wherein said activated maleimide has the formula: ##STR55## wherein: R 2  is a leaving group, R 3  is selected from hydrogen and a protecting group,   R 7  's are hydrogen or up to four optional substituents independently selected from halo, alkyl, hydroxy, alkoxy, haloalkyl, nitro, --NHCO(alkyl), and --NR 9  R 10  where R 9  and R 10  are independently hydrogen or methyl, and   R 8  is hydrogen or an optional substituent selected, from an alkyl, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalaylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group; an alkylglycose residue, a group of the formulae: ##STR56## where: Het signifies a heterocyclyl group,   W signifies NH, S or a bond,   T signifies NH or S,   V signifies O, S, NH, or NCN,   A signifies alkylthio, amino, monoalkylamino or dialkylamino, and   Ar signifies aryl;   R 16  is hydrogen, alkyl, haloalkyl, acetyl, aryl, --CH(aryl) 2 , amino, monoalkylamino, dialkylamino, guanidino, --C(═N(alkoxy-carbonyl))-NH-(alkoxycarbonyl), amidino, hydroxy, carboxy, alkoxycarbonyl or heterocyclyl;   R 14  is hydrogen or an optionally substituted alkyl; or R 8  and R 14  are linked together through a group of the formula: ##STR57## where R 17  and R 18  are independently hydroxy, carboxy, acyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkoxycarbonyl, cyano, amidino or aminocarbonyl, and     n is 1, 2, 3, 4, 5, or 6, p and q are independently 1, 2, 3, or 4, r is 1, 2, or 3, s is 0, 1, 2, or 3, t is 1 or 2, and u is 0 or 1.   
     
     
       14. The method of claim 13 wherein said activated maleimide has the formula: ##STR58## wherein R 3  is --H, methyl (CH 3 ) or a protecting group, R 11  's are hydrogen or up to four substituents independently selected from halo, C 1  to C 4  alkyl, hydroxy, C 1  to C 4  alkoxy, halo, C 1  to C 4  -alkyl, nitro, --NHCO(C 1  -C 4  alkyl) and --NR 9  R 10  where R 9  and R 10  are independently hydrogen or methyl, R 12  is hydrogen or an optional substituent selected, from an alkyl, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group, an alkylglycose residue, a group of the formulae: ##STR59## where: Het signifies a heterocyclyl group, W signifies NH, S or a bond,   T signifies NH or S,   V signifies O, S, NH, or NCN,   A signifies alkylthio, amino, monoalkylamino or dialkylamino, and   Ar signifies aryl;   R 16  is hydrogen, alkyl, haloalkyl, acetyl, aryl, --CH(aryl) 2 , amino, monoalkylamino, dialkylamino, guanidino, --C(═N(alkoxy-carbonyl))-NH-(alkoxycarbonyl), amidino, hydroxy, carboxy, alkoxycarbonyl or heterocyclyl;   R 14  is hydrogen or an optionally substituted alkyl;   or R 8  and R 14  are linked together through a group of the formula: ##STR60## where R 17  and R 18  are independently hydroxy, carboxy, acyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkoxycarbonyl, cyano, amidino or aminocarbonyl, and   n is 1, 2, 3, 4, 5, or 6, p and q are independently 1, 2, 3, or 4, r is 1, 2, or 3, s is 0, 1, 2, or 3, t is 1 or 2, and u is 0 or 1.   
     
     
       15. The method of claim 13 wherein R 5  is --B(OH) 2 . 
     
     
       16. The method of claim 14 wherein R 5  is --B(OH) 2 . 
     
     
       17. The method of claim 15 wherein said reacting is conducted in the presence of a fluoride ion. 
     
     
       18. The method of claim 16 wherein said reacting is conducted in the presence of a fluoride ion. 
     
     
       19. The method of claim 3 wherein said indolylmaleimide has a formula: ##STR61## wherein the bridging moiety represented by ##STR62## is an optionally substituted alkylene, optionally having an internal ether linkage, an internal amino linkage or an internal amide linkage. 
     
     
       20. The method of claim 9 wherein said indolylmaleimide has a formula: ##STR63## wherein the bridging moiety represented by ##STR64## is an optionally substituted alkylene, optionally having an internal ether linkage, an internal amino linkage or an internal amide linkage. 
     
     
       21. The method of making a bisindolylmaleimide according to claim 13 wherein said bisindolylmaleimide has the formula: ##STR65## and said organometallic-3-indole has the formula: ##STR66## wherein the bridging moiety represented by ##STR67## is an optionally substituted alkylene, optionally having an internal ether linkage, an internal amino linkage or an internal amide linkage.